The role of excitatory amino acids (EAAs) in the excitation of monkey spinothalamic tract (STT) neurons following activation of cutaneous primary afferent fibers by noxious and non-noxious stimuli was investigated. The responses of STT neurons to either NMDA or non-NMDA EAA ligands were blocked by infusion of specific antagonists through a microdialysis fiber into the region surrounding the cells. Our results show that blockade of non-NMDA receptors results in a nearly complete elimination of the responses of STT neurons to all stimuli. Blockade of NMDA receptors results in an attenuation of the responses to noxious stimuli but, in addition, prevents the development of the sensitization of STT neurons that is often observed after intradermal injection of capsaicin. These observations further support a role of EAAs in the transmission of sensory information from primary afferent fibers to dorsal horn neurons and a role for NMDA receptors in the generation of hyperalgesia.

1. Responses of spinothalamic tract (STT) neurons to mechanical and thermal stimulation of skin were recorded under urethane and pentobarbital anesthesia in 12 control rats and in 20 rats with experimental neuropathy. Activity of the STT cells in neuropathic rats was recorded 7, 14, and 28 days after inducing the neuropathy by placing four loose ligatures on the sciatic nerve. 2. All neuropathic animals showed guarding of the injured hindpaw and a shorter withdrawal latency from a radiant heat source of the neuropathic hindpaw than that of the sham-operated paw. 3. STT neurons in neuropathic animals showed the most profound changes 7 and 14 days after the nerve ligation. When compared with STT cells in unoperated animals, approximately half of the neurons had high background activity, responses to innocuous stimuli represented a larger percentage of the total evoked activity in wide dynamic range neurons, and the occurrence and magnitude of afterdischarges to mechanical and thermal stimuli were increased. 4. The mean threshold temperatures of heat-evoked responses of the STT cells in neuropathic animals were not different than those of cells from control animals. However, in neuropathic rats, cells reacting to small heat stimuli usually already had afterdischarges. 5. The increase in the background activity of STT cells is consistent with behavioral observations of spontaneous pain in this model of experimental neuropathy. Furthermore, the afterdischarges of STT cells may parallel the prolonged paw withdrawal in response to noxious stimuli that is seen in these animals and that is evidence for hyperalgesia. However, there was no indication of a lowered threshold for thermal stimuli as might be expected if the animals have thermal allodynia. Mechanical allodynia may have resulted from a relative increase in responsiveness to innocuous mechanical stimuli. However, responses to noxious mechanical stimuli were reduced compared with control, at least at 28 days after the ligation. Peripheral and central mechanisms responsible for the changes in responses of STT cells in neuropathic animals are suggested.

1. Activation of neurokinin receptors contributes to the excitation of many dorsal horn neurons by cutaneous sensory stimuli, particularly noxious stimuli. In the present study we investigate the role of neurokinin receptors in the activation of primate spinothalamic tract (STT) neurons by cutaneous mechanical stimuli and by intradermal injection of capsaicin. This was done by testing the responses of these neurons to a battery of cutaneous stimuli before and during infusion by microdialysis of antagonists selective for NK1 and NK2 receptors. 2. The NK1 receptor antagonists cis-3-(2-methoxybenzyl-amino-2-benzhydrylquinuclidine (CP96345) and D-Pro9-[Spiro-y-lactam]-Leu10,Trp11)-Physalaemin(1-11) (GR82334) did not significantly reduce the responses of STT cells to mechanical stimulation of the skin. Both NK1 antagonists did, however, produce a significant reduction in the responses of STT neurons to an intradermal injection of capsaicin. Finally, despite having no effects on responses to mechanical stimuli, both NK1 antagonists prevented the sensitization of the responses to cutaneous stimuli that is usually observed after intradermal injections of capsaicin. 3. The NK2 selective antagonists PhCO-Ala-Ala-D-Trp-Phe-D-Pro-Pro-Nle-NH2 (GR98400) and [Tyr5,D-Trp6,8,9,Lys10]-NKA (4-10) (MEN10376) had effects very similar to those of the NK1 antagonists, but with an important difference. Neither NK2 antagonist affected the responses of STT neurons to noxious or innocuous mechanical stimulation of the skin, but they did reduce the responses to intradermal capsaicin injections. These compounds failed to prevent capsaicin-induced sensitization. In fact, cells exposed to GR98400 or MEN10376 showed unusually sustained increases in the responses to mechanical stimuli after the first capsaicin injection, suggesting that these compounds actually induced sensitization. 4. These results support the contention that both neurokinin receptors participate in the processing of nociceptive information in the dorsal horn, especially responses to strong stimuli such as intradermal injection of capsaicin. NK1 receptors are also involved in the sensitization of STT neurons after peripheral injury. A clearer understanding of the role of NK2 receptors in sensitization requires further studies with improved antagonists.

Nitric oxide (NO) has been proposed to contribute to the development of hyperalgesia by activating the NO/guanosine 3',5'-cyclic monophosphate (cGMP) signal transduction pathway in the spinal cord. We have examined the effects of NO on the responses of primate spinothalamic tract (STT) neurons to peripheral cutaneous stimuli and on the sensitization of STT cells following intradermal injection of capsaicin. The NO level within the spinal dorsal horn was increased by microdialysis of a NO donor, 3-morpholinosydnonimine (SIN-1). SIN-1 enhanced the responses of STT cells to both weak and strong mechanical stimulation of the skin. This effect was preferentially on deep wide dynamic range STT neurons. The responses of none of the neurons tested to noxious heat stimuli were significantly changed when SIN-1 was administered. Intradermal injection of capsaicin increased dramatically the content of NO metabolites, NO-2/NO-3, within the dorsal horn. This effect was attenuated by pretreatment of the spinal cord with a nitric oxide synthase (NOS) inhibitor, NG-nitro-L-arginine methyl ester (L-NAME). Sensitization of STT cells induced by intradermal injection of capsaicin was also prevented by pretreatment of the dorsal horn with the NOS inhibitors, L-NAME or 7-nitroindazole. Blockade of NOS did not significantly affect the responses of STT cells to peripheral stimulation in the absence of capsaicin injection. The data suggest that NO contributes to the development and maintenance of central sensitization of STT cells and the resultant mechanical hyperalgesia and allodynia after peripheral tissue damage or inflammation. NO seems to play little role in signaling peripheral stimuli under physiological conditions.

1. An experimental peripheral neuropathy (EPN) was induced in three monkeys (Macaca fascicularis) by ligation of spinal nerve L7. Behavioral responses to innocuous mechanical stimuli were tested before and after the surgery. Two weeks after the nerve ligation, the activity of spinothalamic tract (STT) neurons was recorded on both sides of the spinal cord with the animal under general anesthesia. Responses of the STT neurons to the following stimuli applied to the skin were recorded: graded mechanical stimuli (brush, press, pinch and squeeze), von Frey filaments of different bending forces (0.077-19.05 g), 5-s heat stimuli ranging from 39 to 53 degrees C, and 15 s cold stimuli (32-8 degrees C). 2. Innocuous mechanical stimulation of the foot did not evoke hindlimb withdrawal in the animals before surgery. Within 24-48 h after nerve ligation, the animals showed hindlimb withdrawal to the same innocuous stimuli. This behavior was more pronounced on the side of the ligation than on the sham-operated side and more frequent during the second week after the surgery. 3. Responses of 51 STT neurons recorded on the side of the ligation (EPN all group) were compared with responses of 33 STT cells recorded on the sham-operated side (control group) and with records from STT neurons in unoperated animals obtained earlier (reference group). Neurons from the EPN all group were divided into two sets according to their rostrocaudal location (EPN R, rostral to L6/7 border, n = 40; EPN C, caudal to L6/7 border, n = 11). 4. Neurons from the EPN all and EPN R groups had significantly higher background frequencies than those from the control and reference groups. Innocuous brush stimuli evoked mean discharge frequencies of approximately 35 Hz in EPN R neurons and only approximately 15 Hz in both control and reference groups. Increased responsiveness of EPN R neurons to innocuous stimuli was also demonstrated by lower thresholds and higher discharge frequencies to von Frey filament stimulation and by discriminative analysis of the responses evoked by graded mechanical stimuli. 5. The responses of the EPN R neurons to heat stimulation of the skin showed decreased thresholds and increased responses to suprathreshold stimuli, resulting in a significant leftward shift of the stimulus-response curve compared with both reference and control groups. The neurons from the control group showed responses comparable to reference group values. 6. Neurons from the reference group tested with the cooling stimuli showed no evoked response above background.(ABSTRACT TRUNCATED AT 400 WORDS)